In recent years, certain drugs have been sold in compositions suitable for forming a drug dispersion for oral inhalation (pulmonary delivery) to treat various conditions in humans. Such pulmonary drug delivery compositions are designed to be delivered by inhalation by the patient of a drug dispersion so that the active drug within the dispersion can reach the lung. It has been found that certain drugs delivered to the lung are readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery is particularly promising for the delivery of active agents (proteins, polypeptides, high-molecular-weight polysaccharides, and nucleic acids) which are difficult to deliver by other routes of administration. Such pulmonary delivery can be effective both for systemic delivery and for localized delivery to treat diseases of the lungs.
Pulmonary drug delivery can itself be achieved by different approaches, including liquid nebulizers, propellant-based metered dose inhalers (MDI's), and dry powder inhaler (DPI) devices. DPIs are particularly promising for delivering drugs that may be readily formulated as dry powders. Many otherwise labile active agents may be stably stored as lyophilized or spray-dried powders by themselves or in combination with suitable powder carriers.
The ability to deliver pharmaceutical compositions as dry powders, however, is problematic in certain respects. The dosage of many pharmaceutical compositions is often critical, so it is desirable that dry powder delivery systems be able to accurately, precisely, and reliably deliver the intended amount of drug. Moreover, many pharmaceutical compositions are quite expensive. Thus, the ability to efficiently formulate, process, package, and deliver the dry powders with a minimal loss of drug is critical.
A particularly promising approach for the pulmonary delivery of dry powder drugs utilizes a hand-held device with a hand pump for providing a source of pressurized gas. The pressurized gas is abruptly released through a powder dispersion device, such as a venturi nozzle, and the dispersed powder made available for patient inhalation. While advantageous in many respects, such hand-held devices are problematic in a number of other respects. The particles being delivered are often less than 5 μm in size, making powder handling and dispersion more difficult than with larger particles. The problems are exacerbated by the relatively small volumes of pressurized gas available using hand-actuated pumps. In particular, venturi dispersion devices are unsuitable for difficult-to-disperse powders when only small volumes of pressurized gas are available with the handpump. Another requirement for hand-held and other powder delivery devices is efficiency. High device efficiency in delivering the drug to the patient with the optimal size distribution for pulmonary delivery is desirable for a commercially viable product. Conventional techniques used to deliver medication do not have the delivery efficiency required for commercialization. The ability to achieve both adequate dispersion and small dispersed volumes is a significant technical challenge that requires that each unit dosage of the powdered composition be readily and reliably dispersible.
Spray drying is a conventional chemical processing unit operation used to produce dry particulate solids from a variety of liquid and slurry starting materials. The use of spray drying for the formulation of dry powder pharmaceuticals, including proteins and peptides for pulmonary administration, is known. Spray drying processes for producing fine powders for inhalation are disclosed in U.S. Pat. Nos. 5,976,574, 5,985,248, 6,001,336, 6,051,256, 6,077,543, and 6,423,344 and PCT Publications WO 96/32149, WO 99/16419, WO 01/00312, WO 01/85136 and in WO 02/09669 which are hereby incorporated in their entirety by reference. Additional spray drying processes are disclosed in WO 97/13503 and U.S. Pat. Nos. 5,622,657, 5,723,269, 6,149,941 and 6,165,511, hereby incorporated in their entirety by reference.
The use of spray drying for the preparation of active agent compositions, including proteins, polypeptides, high molecular weight polysaccharides, and nucleic acids, can be problematic since such active agents are often labile and subject to degradation when exposed to high temperatures and other aspects of the spray drying process. Excessive degradation of the active agents can lead to drug formulations lacking in the requisite purity. It can also be difficult to control particle size and particle size distribution in compositions produced by spray drying. For pulmonary delivery, the average particle size should be maintained below 10 μm, preferably below 5 μm, such as in the range from 0.4 μm to 5 μm, and the amount of the composition comprising particles outside of the target size range should be minimized. Preferably, at least 90% by weight of the powder will have a particle size in the range from 0.1 μm to 7 μm. More preferably, at least 95% will have a size in the range from 0.4 μm to 5 μm. Moreover, it can sometimes be difficult to achieve a desired low moisture content sufficient for physical and chemical stability in the final particulate product, particularly in an economic manner. Also, it has been difficult to produce the small particles necessary for pulmonary delivery in an efficient manner. For high value macromolecular drugs, collection efficiencies (i.e., the amount of particulate drug recovered from the process in a useable form) should be above 80% by weight, preferably above 90% by weight, and desirably above 95% by weight.
Due to the difficulties in particle collection and efficient aerosol dispersion, the use of larger carrier particles (i.e. up to an order of magnitude) such as lactose in combination with the active agent particles is well known in the pulmonary drug delivery field. The combination of these carrier particles with the active agent particles results in a final product consisting of a powder blend of these two constituents. These powder blends are typically prepared by separately producing each of the blend constituents, and then combining the two constituents in yet another processing step, typically mechanically mixing the two dry particle constituents in a mixer such as a Turbula mixer under optimized conditions. However, there exists a need to effectively blend significant quantities of respirable particle sized powders.
While spray drying has been used to prepare fine powders of active agents in laboratory scale equipment, commercial spray dryers are not designed to produce such fine powders in the pulmonary size range. In scaling up a spray-drying process from the laboratory or even pilot plant scale to the commercial scale, certain inefficiencies may become manifest. For example, the solvent content of the product may increase if the drying efficiency is not adequately scaled. As part of the scale-up to commercial processing, which may include as much as a tenfold or greater increase in throughput from a pilot-plant scale, careful consideration must be given in order to preserve product properties.
Various atomizers have been used in the spray drying of pharmaceutical powders. Droplet size and droplet size distribution are determined by the selection of the atomizer and operating conditions. These include gas assisted two-fluid nozzles, rotary atomizers and ultrasonic atomizers comprising an oscillating horn to create surface instabilities resulting in droplet formation. Examples of each of these various atomizers are disclosed in the patents cited above.
Sonic air-assisted two-fluid atomization nozzles (two-fluid nozzles) involve impacting liquid bulk with high velocity gas, utilizing the kinetic energy of a sonic or supersonic velocity gas stream to create the liquid surface area. Sprays of low viscosity feed are characterized by low mean droplet sizes. Formation of sprays having a mass median diameter of 15-20 microns are well established for such two-fluid nozzles. With more viscous feeds, larger mean droplet sizes are produced with a wider particle size distribution. Among the variables affecting mean droplet size for two-fluid nozzles, the air to liquid mass ratio (Mair:Mliq) and design details of the given atomizer are perhaps the most important variables.
In rotary atomization, the feed liquid is centrifugally accelerated to high velocity before being discharged into an air-gas atmosphere. The liquid is distributed centrally on a rotating wheel/disc/cup and extends over the rotating surface as a thin film. Operating variables that influence droplet size produced from atomizer wheels are speed of rotation, wheel diameter, wheel design (number and geometry of vanes or bushings), feed rate, viscosity of feed and air, density of feed and air, and surface tension of feed. Two-fluid nozzles are capable of producing smaller droplets compared to rotary atomizers. It is perhaps for their ability to produce smaller droplets that two-fluid nozzles are currently more commonly used in spray drying applications for producing particles for pulmonary administration.
More recently, interest has focused on electrically assisted ultrasonic atomizers. Such interest has in part been prompted by the need to develop a technique to atomize products that are non Newtonian, highly viscous, and have long chain molecular structures, and that form only strings or filaments from rotary atomizers and liquids that require very high pressure for effective atomization from pressure nozzles.
Whichever atomizer is selected, its design must be scaled when moving from laboratory or pilot scale capacity to larger, commercial scales. Careful consideration must be given to ensure satisfactory maintenance of the initial droplet formation. Failure to provide suitable initial droplet conditions could lead to significant differences in product characteristics of the final spray-dried particulates.
The above describes some of the problems currently encountered in the development of spray drying processes for pharmaceutical application, particularly with respect to spray drying powders for pulmonary administration. Moreover, it can be difficult to achieve a desired low moisture content required for physical and chemical stability in the final particulate product, particularly in an economic manner. Finally and perhaps most importantly, it has been difficult to produce the small particles necessary for pulmonary delivery in an efficient manner on a large scale suitable for commercial applications.
It is therefore desirable to provide improved methods and apparatuses for the spray drying of pharmaceuticals for use in pulmonary and other drug delivery applications. In particular, it is desirable to provide improved methods and apparatuses suitable for such applications at the commercial plant scale which maintain product properties observed at smaller pilot scales.
It is further desirable to produce a uniform powder blend for pharmaceutical applications, particularly for particles sized for respiratory administration, which can be produced in a single step. Such a simplified process eliminates the need for intermediate storage, reduces the risk of product contamination and/or product loss, and reduces capital equipment costs thereby reducing the time and costs of the current multi-step blending processes. Furthermore, such single step production of powder blends eliminates the optimization of current mechanical blending techniques, which is an extremely time consuming process.